Alkaline cleavage of pseudosapogenin oxidation products



Patented Jan( 19 1954- A A r I ALKALINE CLEAVAGE F PSEUDOSAPO- GENIN OXIDATION PRODUCTS Monroe E. Wall, Oreland, Pa.,, assignor to the United States of America as represented by the Secretary of Agriculture No Drawing. Application February 20, 1953, Serial No. 338,172

7 Claims. (01. 260-89741) (Granted under Title 35, U. S. Codev (1 952),

I see. 266) p A non-exclusive, irrevocable, royalty-free by the action of either acid or alkali in a I license intheinvention herein described, for all methanolic or ethanolic solution. As indicated, governmental purposes, throughout the world, the yield in this step is very poor, usually about with the power to grant sublicenses for such pur- 30%, because of the formation of large amounts poses, is hereby granted to the Government of 5 of the undesirable ld-methoxyor ld-ethoxy dethe United States of America. rivatives by reaction of the desired zi -pregneno- This invention is related to the conversion of lone with the methanol or ethanol used as a solsapogenins to n -pregnenolones. uent'and reaction medium in this step. It: is

An object of this invention is to provide an with this third step that the present invention is improved process for making n -pregnenolones concerned.

from sapogenins. I In step 3 the cleavage isbest accomplished in a One of the facts that makes steroidal sapohomogeneous solution containing the alkali and genins'useful for the production of cortisone and the oxidized pseudosapogenin. The solvent used sex hormones is that they are convertible to Ale. should readily dissolve the alkali and oxidized pregnenolones. This conversion is conventionally seudosapogenin and should be inert to them and carried out in three steps as is illustrated below the final product. Methanol and ethanol, the

with smilagenin, a typical steroidal sapogenin. preferred solvents of the prior art, have suit- Other steroidal sapogenins react in the same way able solvent properties but are not chemically to yield analogous A -p'regnenolones. I inert. They react with the A -pregnenolones to CH3 0H3 (13H:

F -CH3 -(QH rCH-OEQOAC E t 0 E l /O 0 A Step 1 D D. 5

AcO,

Sapogenin (smilagenin) P seudosapogenin [Step2 on; 3 11;- C==OA pre enolone (i=0: I I CHa-.,

Oxidized pseudosapogcnin I! O R l6alkoxy derivative In ste 1 the sapogenin is heated at about 200 produce large amounts of the undesirable 16- C. with. acetic anhydride to open ring F. In step alkoxy derivatives, thus lowering the yield of 2 the resulting pseudosapogenin is oxidized with the desired products. chromium trioxide to open ring E. Then, in step I have now discovered that the above-men- 3, the conventional procedure is to cleave the tioned undesired-side reaction can be eliminated ester linkages in the oxidized pseudosapogenin and the yield and purity of thedesired A pregiienolones can be greatly increased by proper choice of the solvent used in step 3 of the process outlined above. Suitable solvents include the tertiary alkanols having not more than six carbon atoms, pyridine and the lower alkyl pyridines. The higher homologs of these soluents are unsuitable because they do not readily dissolve alkali. The suitable solvents can be used in the pure form but their suitability is increased by the addition of not more than about 5% of water. This greatly increases the solubility of alkali in the solvent but at the same time it decreases the solubility of the oxidized pseudosapogenin being treated. Hence, in practice, the optimum amount of water will be found to depend on the solvent, the alkali and the sapogenin used. While any alkali metal hydroxide, carbonate or bicarbonate can be used, I prefer to use potassium hydroxide because of its ready solubility and its high reactivity.

While the reaction mixture may be warmed if desired, I have found that the reaction proceeds rapidly and smoothly at ordinary room temperature and that heating sometimes lowers the yield of the desired product.

It has also been observed that the reaction mixture need not be entirely homogeneous, provided that adequate agitation and mixing is provided. Thus, the entire amount of alkali or oxidized pseudosapogenin need not be dissolved, provided that there is appreciable solubility, because that part which is dissolved will react and be consumed, thus allowing more to be dissolved. In this way the entire amount is soon used up and the overall efiect is almost as good as if the mixture had been homogeneous.

Example I Twenty grams of diosgenin acetate and 100 ml. of acetic anhydride were heated hours at 200 C. in a sealed vessel. After being cooled, the acetic anhydride was distilled in vacuum and the remaining pseudosapogenin was dissolved in 200 ml, of acetic acid to which 5 g. of sodium acetate had been added. A solution of 8 g. of chromium trioxide in 30 ml. of 80% aqueous acetic acid was added dropwise, with agitation and cooling, over a period of 30 minutes and at a temperature of about C. The reaction mixture was then allowed to stand 1 hr. at room temperature, after which an equal volume of water was added, the excess chromic acid was neutralized with 3 g. of sodium bisulfite and the mixture was extracted with ether. After being washed with dilute sodium bicarbonate and with water, the ether solution was evaporated to dryness, leaving a sirupy residue of oxidized pseudosapogenin. This was dissolved in 500 ml. of tertiary-butanol. To this solution was added a solution of g. of potassium hydroxide and 20 g. of water in 500 m1. of tertiary-butanol. The resultant mixture was vigorously stirred at room temperature (ZS-28 C.) for 3 hr., after which two volumes of water were added and the mixture was extracted with ether. After being washed with water the ether solution was evaporated to dryness and the solid residue was dissolved in ml. of pyridine to which was added 25 ml. of acetic anhydride. After being left overnight the resultant A -pregnadien-3s-o1-3-acetoxy-20-one was recovered by diluting with water and extracting with ether. The ether extract was washed with dilute hydrochloric acid, dilute sodium bicarbonate and water; dried with anhydrous sodium sulfate and evaporated to dryness. The

crude product thus obta ned was purified by dissolving it in benzene and chromatographing it on Florosil (magnesium silicate) The final product was 10.74 g. of M -pregnadien-35-ol-3-acetoxy-20-one which by ultraviolet assay was found to be 94% pure. Recrystallization from methanol yielded 8.5 g. of substantially 100% pure material, The yield, based on the ultraviolet assay, was 74.5% of the theoretical from diosgenin acetate of purity.

Example II Example III By proceeding substantially as in Exampl I sarsasapogenin acetate was converted to A pregnen-3fi-ol-3-acetate-20one.

Example IV By proceeding substantially as in Example I hecosenin acetate was converted to A -allopregnen-3B-ol-3-acetate-12,20-dione.

Example V Ten grams of oxidized pseudotigogenin were dissolved in a pyridine solution prepared by shaking 1 liter of pyridine with 1 liter of 5% aqueous potassium hydroxide and discarding the aqueous layer. After being stirred for 3 hr., an equal volume of water was added to the solution and the Whole was extracted with ether. The ether extract was washed, dried and evaporated and the product was acetylated and chromatographed as in Example I to yield 3.0 g. of A allopregnen-3fi-ol-3-acetate-20-one.

I claim:

1. In a process for making a A -pregnenolone from a steroidal sapogenin, the steps comprising cleaving an oxidized pseudosapogenin by the ac tion of alkali in a solvent selected from the group consisting of aliphatic tertiary alcohols having not more than six carbon atoms, pyridine and lower alkylypyridines.

2. The process of claim 1 wherein the solvent is tertiary butanol.

3. The process of claim 1 wherein the solvent is pyridine.

4:. The process for making a A -pregnenolone from an oxidized pseudosapogenin which comprises treating the oxidized pseudosapogenin with an alkali in a solvent selected from the group consisting of aliphatic tertiary alcohols, pyridine and lower alkylpyridines.

5. The process of claim 4 wherein the alkali is potassium hydroxide.

6. The process of claim 4 wherein the solvent i tertiary butanol.

'7. The process of claim 4 wherein the solvent is pyridine.

MONROE E. WALL.

No references cited. 

1. IN A PROCESS FOR MAKING A $16-PREGNENOLONE FROM A STEROIDAL SAPOGENIN, THE STEPS COMPRISING CLEAVING AN OXIDIZED PSEUDOSAPOGENIN BY THE ACTION OF ALKALI IN A SOLVENT SELECTED FROM THE GROUP CONSISTING OF ALIPHATIC TERTIARY ALCOHOLS HAVING NOT MORE THAN SIX CARBON ATOMS, PYRIDINE AND LOWER ALKYLYPYRIDINES. 